tbuckley/cabot-search huggingface dataset:
Exocrine Proteins Including Trypsin(ogen) as a Key Biomarker in Type 1 Diabetes
Authors: Lilianna Bakinowska, Tanwi Vartak, Thato Phuthego, Michelle Taylor, Kyla Chandler, Samual T. Jerram, Steven Williams, Marc Feldmann, Desmond G. Johnson, Kashyap A. Patel, Alistair J.K. Williams, Anna E. Long, R. David Leslie, Kathleen M. Gillespie, Richard David Leslie, Mohammed I Hawa, Paolo Pozzilli, Henning Beck-Nielsen, Knud Yderstraede, Steven Hunter, David Hadden, Raffaella Buzzetti, Werner Scherbaum, Hubert Kolb, Nanette C. Schloot, Jochen Seissler, Guntram Schernthaner, Jaakko Tuomilehto, Cinzia Sarti, Alberto De Leiva, Eulalia Brugues, Didac Mauricio, Charles Thivolet, Isabel Wilson, Rachel Aitken, Clare Megson, Chitrabhanu Ballav, Atanu Dutta, Michelle Russell-Taylor, Rachel Besser, James Bursell, Shanthi Chandran, Sejal Patel, Anne Smith, Manohara Kenchaiah, Gomathi Margabanthu, Foteini Kavvoura, Chandan Yaliwal
Journal: Diabetes Care (2023)

OBJECTIVE Proteomic profiling can identify useful biomarkers. Monozygotic (MZ) twins discordant for a condition represent an ideal test population. We aimed to investigate and validate proteomic profiling in twins with type 1 diabetes and in other well-characterized cohorts. RESEARCH DESIGN AND METHODS A broad, multiplex analysis of 4,068 proteins in serum samples from MZ twins concordant (n = 43) and discordant (n = 27) for type 1 diabetes identified major differences that were subsequently validated by a trypsin(ogen) assay in MZ pairs concordant (n = 39) and discordant (n = 42) for type 1 diabetes, individuals at risk for (n = 195) and with (n = 990) type 1 diabetes, as well as individuals with non–insulin-requiring adult-onset diabetes diagnosed as either autoimmune (n = 96) or type 2 (n = 291). RESULTS Proteomic analysis identified major differences between exocrine enzyme levels in discordant MZ twin pairs despite a strong correlation between twins, whether concordant or discordant for type 1 diabetes (P &amp;lt; 0.01 for both). In validation experiments, trypsin(ogen) levels were lower in twins with diabetes than in the co-twin without diabetes (P &amp;lt; 0.0001) and healthy control participants (P &amp;lt; 0.0001). In recently diagnosed participants, trypsin(ogen) levels were lower than in control participants across a broad age range. In at-risk relatives, levels &amp;lt;15 ng/mL were associated with an increased risk of progression (uncorrected P = 0.009). Multiple linear regression in recently diagnosed participants showed that trypsin(ogen) levels were associated with insulin dose and diabetic ketoacidosis, while age and BMI were confounders. CONCLUSIONS Type 1 diabetes is associated with altered exocrine function, even before onset. Twin data suggest roles for genetic and nongenetically determined factors. Exocrine/endocrine interactions are important underinvestigated factors in type 1 diabetes.
A symbolic Neanderthal accumulation of large herbivore crania
Authors: Enrique Baquedano, Juan L. Arsuaga, Alfredo Pérez-González, César Laplana, Belén Márquez, Rosa Huguet, Sandra Gómez-Soler, Lucía Villaescusa, M. Ángeles Galindo-Pellicena, Laura Rodríguez, Rebeca García-González, M.-Cruz Ortega, David M. Martín-Perea, Ana I. Ortega, Lucía Hernández-Vivanco, Gonzalo Ruiz-Liso, Juan Gómez-Hernanz, José I. Alonso-Martín, Ana Abrunhosa, Abel Moclán, Ana I. Casado, Marina Vegara-Riquelme, Ana Álvarez-Fernández, Ángel C. Domínguez-García, Diego J. Álvarez-Lao, Nuria García, Paloma Sevilla, Hugues-Alexandre Blain, Blanca Ruiz-Zapata, M. José Gil-García, Adrián Álvarez-Vena, Teresa Sanz, Rolf Quam, Tom Higham
Journal: Nature Human Behaviour (2023)

Abstract This work examines the possible behaviour of Neanderthal groups at the Cueva Des-Cubierta (central Spain) via the analysis of the latter’s archaeological assemblage. Alongside evidence of Mousterian lithic industry, Level 3 of the cave infill was found to contain an assemblage of mammalian bone remains dominated by the crania of large ungulates, some associated with small hearths. The scarcity of post-cranial elements, teeth, mandibles and maxillae, along with evidence of anthropogenic modification of the crania (cut and percussion marks), indicates that the carcasses of the corresponding animals were initially processed outside the cave, and the crania were later brought inside. A second round of processing then took place, possibly related to the removal of the brain. The continued presence of crania throughout Level 3 indicates that this behaviour was recurrent during this level’s formation. This behaviour seems to have no subsistence-related purpose but to be more symbolic in its intent.
Urban scaling laws arise from within-city inequalities
Authors: Martin Arvidsson, Niclas Lovsjö, Marc Keuschnigg
Journal: Nature Human Behaviour (2023)

Abstract Theories of urban scaling have demonstrated remarkable predictive accuracy at aggregate levels. However, they have overlooked the stark inequalities that exist within cities. Human networking and productivity exhibit heavy-tailed distributions, with some individuals contributing disproportionately to city totals. Here we use micro-level data from Europe and the United States on interconnectivity, productivity and innovation in cities. We find that the tails of within-city distributions and their growth by city size account for 36–80% of previously reported scaling effects, and 56–87% of the variance in scaling between indicators of varying economic complexity. Providing explanatory depth to these findings, we identify a mechanism—city size-dependent cumulative advantage—that constitutes an important channel through which differences in the size of tails emerge. Our findings demonstrate that urban scaling is in large part a story about inequality in cities, implying that the causal processes underlying the heavier tails in larger cities must be considered in explanations of urban scaling. This result also shows that agglomeration effects benefit urban elites the most, with the majority of city dwellers partially excluded from the socio-economic benefits of growing cities.
Th2-skewed T cells correlate with B cell response to α-Gal and tick antigens in α-Gal syndrome
Authors: Danijela Apostolovic, Jeanette Grundström, Mensiena B. Gea Kiewiet, Marija Perusko, Carl Hamsten, Maria Starkhammar, Staffan Paulie, Marianne van Hage
Journal: Journal of Clinical Investigation (2023)

Tick bites have been shown to transmit a novel form of severe food allergy, the galactose-α-1,3-galactose (α-Gal) syndrome (AGS). Cellular responses to α-Gal in patients with AGS have, to date, not been thoroughly scrutinized. Therefore, we investigated T and B cell proliferation, activation, and cytokine profiles in response to tick protein extract (TE) and α-Gal-free TE in patients with AGS and in healthy controls. T and B cells from both patients and controls proliferated in response to TE, but significantly more in patients with AGS. B cell proliferation, but not T cell proliferation, in patients with AGS was reduced by removing α-Gal from the TE. In addition, TE induced a clear Th2 cytokine profile in patients with AGS. Expression of CD23 by B cells correlated only to T cell proliferation. However, both B cell proliferation and CD23 expression were reduced when CD40L and IL-4 were blocked. A large portion of the IgG1 and IgE antibodies binding TE in patients with AGS were directed against the α-Gal epitope. We have, for what we believe to be the first time, investigated T and B cell responses to α-Gal carrying tick proteins in patients with AGS, which will be essential for the understanding of the immune response against an allergenic carbohydrate transmitted by ticks.
Antigen specificity and cross-reactivity drive functionally diverse anti–Aspergillus fumigatus T cell responses in cystic fibrosis
Authors: Carsten Schwarz, Patience Eschenhagen, Henrijette Schmidt, Thordis Hohnstein, Christina Iwert, Claudia Grehn, Jobst Roehmel, Eva Steinke, Mirjam Stahl, Laura Lozza, Ekaterina Tikhonova, Elisa Rosati, Ulrik Stervbo, Nina Babel, Jochen G. Mainz, Hilmar Wisplinghoff, Frank Ebel, Lei-Jie Jia, Matthew G. Blango, Peter Hortschansky, Sascha Brunke, Bernhard Hube, Axel A. Brakhage, Olaf Kniemeyer, Alexander Scheffold, Petra Bacher
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDThe fungus Aspergillus fumigatus causes a variety of clinical phenotypes in patients with cystic fibrosis (pwCF). Th cells orchestrate immune responses against fungi, but the types of A. fumigatus-specific Th cells in pwCF and their contribution to protective immunity or inflammation remain poorly characterized.METHODSWe used antigen-reactive T cell enrichment (ARTE) to investigate fungus-reactive Th cells in peripheral blood of pwCF and healthy controls.RESULTSWe show that clonally expanded, high-avidity A. fumigatus-specific effector Th cells, which were absent in healthy donors, developed in pwCF. Individual patients were characterized by distinct Th1-, Th2-, or Th17-dominated responses that remained stable over several years. These different Th subsets target different A. fumigatus proteins, indicating that differential antigen uptake and presentation directs Th cell subset development. Patients with allergic bronchopulmonary aspergillosis (ABPA) are characterized by high frequencies of Th2 cells that cross-recognize various filamentous fungi.CONCLUSIONOur data highlight the development of heterogenous Th responses targeting different protein fractions of a single fungal pathogen and identify the development of multispecies cross-reactive Th2 cells as a potential risk factor for ABPA.FUNDINGGerman Research Foundation (DFG), under Germany's Excellence Strategy (EXC 2167-390884018 "Precision Medicine in Chronic Inflammation" and EXC 2051-390713860 "Balance of the Microverse"); Oskar Helene Heim Stiftung; Christiane Herzog Stiftung; Mukoviszidose Institut gGmb; German Cystic Fibrosis Association Mukoviszidose e.V; German Federal Ministry of Education and Science (BMBF) InfectControl 2020 Projects AnDiPath (BMBF 03ZZ0838A+B).
Early detection of visual impairment in young children using a smartphone-based deep learning system
Authors: Wenben Chen, Ruiyang Li, Qinji Yu, Andi Xu, Yile Feng, Ruixin Wang, Lanqin Zhao, Zhenzhe Lin, Yahan Yang, Duoru Lin, Xiaohang Wu, Jingjing Chen, Zhenzhen Liu, Yuxuan Wu, Kang Dang, Kexin Qiu, Zilong Wang, Ziheng Zhou, Dong Liu, Qianni Wu, Mingyuan Li, Yifan Xiang, Xiaoyan Li, Zhuoling Lin, Danqi Zeng, Yunjian Huang, Silang Mo, Xiucheng Huang, Shulin Sun, Jianmin Hu, Jun Zhao, Meirong Wei, Shoulong Hu, Liang Chen, Bingfa Dai, Huasheng Yang, Danping Huang, Xiaoming Lin, Lingyi Liang, Xiaoyan Ding, Yangfan Yang, Pengsen Wu, Feihui Zheng, Nick Stanojcic, Ji-Peng Olivia Li, Carol Y. Cheung, Erping Long, Chuan Chen, Yi Zhu, Patrick Yu-Wai-Man, Ruixuan Wang, Wei-shi Zheng, Xiaowei Ding, Haotian Lin
Journal: Nature Medicine (2023)
A phenome-wide comparative analysis of genetic discordance between obesity and type 2 diabetes
Authors: Daniel E. Coral, Juan Fernandez-Tajes, Neli Tsereteli, Hugo Pomares-Millan, Hugo Fitipaldi, Pascal M. Mutie, Naeimeh Atabaki-Pasdar, Sebastian Kalamajski, Alaitz Poveda, Tyne W. Miller-Fleming, Xue Zhong, Giuseppe N. Giordano, Ewan R. Pearson, Nancy J. Cox, Paul W. Franks
Journal: Nature Metabolism (2023)

Abstract Obesity and type 2 diabetes are causally related, yet there is considerable heterogeneity in the consequences of both conditions and the mechanisms of action are poorly defined. Here we show a genetic-driven approach defining two obesity profiles that convey highly concordant and discordant diabetogenic effects. We annotate and then compare association signals for these profiles across clinical and molecular phenotypic layers. Key differences are identified in a wide range of traits, including cardiovascular mortality, fat distribution, liver metabolism, blood pressure, specific lipid fractions and blood levels of proteins involved in extracellular matrix remodelling. We find marginal differences in abundance of Bacteroidetes and Firmicutes bacteria in the gut. Instrumental analyses reveal prominent causal roles for waist-to-hip ratio, blood pressure and cholesterol content of high-density lipoprotein particles in the development of diabetes in obesity. We prioritize 17 genes from the discordant signature that convey protection against type 2 diabetes in obesity, which may represent logical targets for precision medicine approaches.
Persistent mutation burden drives sustained anti-tumor immune responses
Authors: Noushin Niknafs, Archana Balan, Christopher Cherry, Karlijn Hummelink, Kim Monkhorst, Xiaoshan M. Shao, Zineb Belcaid, Kristen A. Marrone, Joseph Murray, Kellie N. Smith, Benjamin Levy, Josephine Feliciano, Christine L. Hann, Vincent Lam, Drew M. Pardoll, Rachel Karchin, Tanguy Y. Seiwert, Julie R. Brahmer, Patrick M. Forde, Victor E. Velculescu, Valsamo Anagnostou
Journal: Nature Medicine (2023)

Abstract Tumor mutation burden is an imperfect proxy of tumor foreignness and has therefore failed to consistently demonstrate clinical utility in predicting responses in the context of immunotherapy. We evaluated mutations in regions of the genome that are unlikely to undergo loss in a pan-cancer analysis across 31 tumor types ( n = 9,242) and eight immunotherapy-treated cohorts of patients with non-small-cell lung cancer, melanoma, mesothelioma, and head and neck cancer ( n = 524). We discovered that mutations in single-copy regions and those present in multiple copies per cell constitute a persistent tumor mutation burden (pTMB) which is linked with therapeutic response to immune checkpoint blockade. Persistent mutations were retained in the context of tumor evolution under selective pressure of immunotherapy and tumors with a high pTMB content were characterized by a more inflamed tumor microenvironment. pTMB imposes an evolutionary bottleneck that cancer cells cannot overcome and may thus drive sustained immunologic tumor control in the context of immunotherapy.
Comprehensive analysis of mutational signatures reveals distinct patterns and molecular processes across 27 pediatric cancers
Authors: Venu Thatikonda, S. M. Ashiqul Islam, Robert J. Autry, Barbara C. Jones, Susanne N. Gröbner, Gregor Warsow, Barbara Hutter, Daniel Huebschmann, Stefan Fröhling, Marcel Kool, Mirjam Blattner-Johnson, David T. W. Jones, Ludmil B. Alexandrov, Stefan M. Pfister, Natalie Jäger
Journal: Nature Cancer (2023)

Abstract Analysis of mutational signatures can reveal underlying molecular mechanisms of the processes that have imprinted the somatic mutations found in cancer genomes. Here, we analyze single base substitutions and small insertions and deletions in pediatric cancers encompassing 785 whole-genome sequenced tumors from 27 molecularly defined cancer subtypes. We identified only a small number of mutational signatures active in pediatric cancers, compared with previously analyzed adult cancers. Further, we report a significant difference in the proportion of pediatric tumors showing homologous recombination repair defect signatures compared with previous analyses. In pediatric leukemias, we identified an indel signature, not previously reported, characterized by long insertions in nonrepeat regions, affecting mainly intronic and intergenic regions, but also exons of known cancer genes. We provide a systematic overview of COSMIC v.3 mutational signatures active across pediatric cancers, which is highly relevant for understanding tumor biology and enabling future research in defining biomarkers of treatment response.
Idiopathic pulmonary fibrosis: state of the art for 2023
Authors: Anna J. Podolanczuk, Carey C. Thomson, Martine Remy-Jardin, Luca Richeldi, Fernando J. Martinez, Martin Kolb, Ganesh Raghu
Journal: European Respiratory Journal (2023)

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease characterised by worsening respiratory symptoms and physiological impairment. Increasing awareness of the clinical manifestations of IPF, more widespread use of computed tomography scans and other potential factors have contributed to a rising prevalence of IPF over the last two decades, especially among people over the age of 65 years. Significant advances in the understanding of the pathobiology of IPF have emerged, and multiple genetic and nongenetic contributors have been identified. The individual patient course and the rate of disease progression in IPF are often unpredictable and heterogeneous. The rate of lung function decline is further modified by treatment with antifibrotic therapies, which have been shown to slow down disease progression. The presence of comorbid conditions may increase symptom burden and impact survival. Clinical monitoring at regular intervals to assess for disease progression by worsening symptoms, physiological parameters and/or radiological features is essential to assess the natural disease course and to guide further management, including prompt detection of complications and comorbid conditions that warrant additional treatment considerations, and timely consideration of referral to palliative care and lung transplantation for the appropriate patient. More studies are needed to determine whether early detection of IPF might improve patient outcomes. The purpose of this concise clinical review is to provide an update on IPF diagnosis, epidemiology, natural history and treatment in the context of new knowledge and latest clinical practice guidelines.
Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains
Authors: Ditte Demontis, G. Bragi Walters, Georgios Athanasiadis, Raymond Walters, Karen Therrien, Trine Tollerup Nielsen, Leila Farajzadeh, Georgios Voloudakis, Jaroslav Bendl, Biau Zeng, Wen Zhang, Jakob Grove, Thomas D. Als, Jinjie Duan, F. Kyle Satterstrom, Jonas Bybjerg-Grauholm, Marie Bækved-Hansen, Olafur O. Gudmundsson, Sigurdur H. Magnusson, Gisli Baldursson, Katrin Davidsdottir, Gyda S. Haraldsdottir, Esben Agerbo, Gabriel E. Hoffman, Søren Dalsgaard, Joanna Martin, Marta Ribasés, Dorret I. Boomsma, Maria Soler Artigas, Nina Roth Mota, Daniel Howrigan, Sarah E. Medland, Tetyana Zayats, Veera M. Rajagopal, Alexandra Havdahl, Alysa Doyle, Andreas Reif, Anita Thapar, Bru Cormand, Calwing Liao, Christie Burton, Claiton H. D. Bau, Diego Luiz Rovaris, Edmund Sonuga-Barke, Elizabeth Corfield, Eugenio Horacio Grevet, Henrik Larsson, Ian R. Gizer, Irwin Waldman, Isabell Brikell, Jan Haavik, Jennifer Crosbie, James McGough, Jonna Kuntsi, Joseph Glessner, Kate Langley, Klaus-Peter Lesch, Luis Augusto Rohde, Mara H. Hutz, Marieke Klein, Mark Bellgrove, Martin Tesli, Michael C. O’Donovan, Ole Andreas Andreassen, Patrick W. L. Leung, Pedro M. Pan, Ridha Joober, Russel Schachar, Sandra Loo, Stephanie H. Witt, Ted Reichborn-Kjennerud, Tobias Banaschewski, Ziarih Hawi, Mark J. Daly, Ole Mors, Merete Nordentoft, Ole Mors, David M. Hougaard, Preben Bo Mortensen, Mark J. Daly, Stephen V. Faraone, Hreinn Stefansson, Panos Roussos, Barbara Franke, Thomas Werge, Benjamin M. Neale, Kari Stefansson, Anders D. Børglum
Journal: Nature Genetics (2023)
Intrathymic dendritic cell-biased precursors promote human T cell lineage specification through IRF8-driven transmembrane TNF
Authors: Kai Ling Liang, Juliette Roels, Marieke Lavaert, Tom Putteman, Lena Boehme, Laurentijn Tilleman, Imke Velghe, Valentina Pegoretti, Inge Van de Walle, Stephanie Sontag, Jolien Vandewalle, Bart Vandekerckhove, Georges Leclercq, Pieter Van Vlierberghe, Claude Libert, Filip Van Nieuwerburgh, Roman Fischer, Roland E. Kontermann, Klaus Pfizenmaier, Gina Doody, Martin Zenke, Tom Taghon
Journal: Nature Immunology (2023)
Impaired dynamics of precapillary sphincters and pericytes at first-order capillaries predict reduced neurovascular function in the aging mouse brain
Authors: Changsi Cai, Stefan Andreas Zambach, Søren Grubb, Lechan Tao, Chen He, Barbara Lykke Lind, Kirsten Joan Thomsen, Xiao Zhang, Bjørn Olav Hald, Reena Murmu Nielsen, Kayeon Kim, Anna Devor, Micael Lønstrup, Martin Johannes Lauritzen
Journal: Nature Aging (2023)
Dermal macrophages set pain sensitivity by modulating the amount of tissue NGF through an SNX25–Nrf2 pathway
Authors: Tatsuhide Tanaka, Hiroaki Okuda, Ayami Isonishi, Yuki Terada, Masahiro Kitabatake, Takeaki Shinjo, Kazuya Nishimura, Shoko Takemura, Hidemasa Furue, Toshihiro Ito, Kouko Tatsumi, Akio Wanaka
Journal: Nature Immunology (2023)

Abstract Cross-talk between peripheral neurons and immune cells is important in pain sensation. We identified Snx25 as a pain-modulating gene in a transgenic mouse line with reduced pain sensitivity. Conditional deletion of Snx25 in monocytes and macrophages, but not in peripheral sensory neurons, in mice ( Snx25 cKO mice) reduced pain responses in both normal and neuropathic conditions. Bone marrow transplantation using Snx25 cKO and wild-type mice indicated that macrophages modulated pain sensitivity. Expression of sorting nexin (SNX)25 in dermal macrophages enhanced expression of the neurotrophic factor NGF through the inhibition of ubiquitin-mediated degradation of Nrf2, a transcription factor that activates transcription of Ngf . As such, dermal macrophages set the threshold for pain sensitivity through the production and secretion of NGF into the dermis, and they may cooperate with dorsal root ganglion macrophages in pain perception.
A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain
Authors: Xueming Hu, Lixia Du, Shenbin Liu, Zhou Lan, Kaikai Zang, Jing Feng, Yonghui Zhao, Xingliang Yang, Zili Xie, Peter L. Wang, Aaron M. Ver Heul, Lvyi Chen, Vijay K. Samineni, Yan-Qing Wang, Kory J. Lavine, Robert W. Gereau, Gregory F. Wu, Hongzhen Hu
Journal: Journal of Clinical Investigation (2023)

Microglia, resident macrophages of the CNS, are essential to brain development, homeostasis, and disease. Microglial activation and proliferation are hallmarks of many CNS diseases, including neuropathic pain. However, molecular mechanisms that govern the spinal neuroimmune axis in the setting of neuropathic pain remain incompletely understood. Here, we show that genetic ablation or pharmacological blockade of transient receptor potential vanilloid type 4 (TRPV4) markedly attenuated neuropathic pain-like behaviors in a mouse model of spared nerve injury. Mechanistically, microglia-expressed TRPV4 mediated microglial activation and proliferation and promoted functional and structural plasticity of excitatory spinal neurons through release of lipocalin-2. Our results suggest that microglial TRPV4 channels reside at the center of the neuroimmune axis in the spinal cord, which transforms peripheral nerve injury into central sensitization and neuropathic pain, thereby identifying TRPV4 as a potential new target for the treatment of chronic pain.